Benzoylpiperidylalkylindoles

ABSTRACT

New benzoylpiperidylalkylindoles and related compounds possessing tranquilizing, anti-hypertensive and analgesic properties and a process for the preparation thereof are described.

This is a continuation in part of application Ser. No. 594,042, filedJuly 8, 1975 now abandoned.

This invention relates to benzoylpiperidylalkylindoles and relatedcompounds possessing tranquilizing properties and to a process for thepreparation thereof. Additionally, some compounds of the invention alsodemonstrate antihypertensive and analgesic properties.

To the best of our knowledge, the compounds of the present inventionhave not heretofore been described. Indoles exhibiting action on thecardiovascular system are mentioned in U.S. Pat. No. 3,527,761 (1970).U.S. Pat. Nos. 3,188,313 (1965) and 3,217,011 (1965) describe 1-[1,2 and3-indolyl]-lower piperazine derivatives and1-(indolylglyoxalyl)piperidines, respectively as having importantbiological activity. Additionally, U.S. Pat. No. 3,821,387 (1974)describes 3-(omegasubstituted alkyl)-indoles as being useful in thetreatment of Parkinsonism. However, the compounds of the presentinvention have substantial structural differences with respect to theprior art.

The compounds of the invention conform to the general formula ##STR1##wherein X is C=O or CHOH; R is hydrogen or methyl; R₁ and R₂ are thesame or different and stand for hydrogen, halogen, straight or branchedchain alkyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms,trifluoromethyl, hydroxy, phenoxy or phenyl; R₃ and R₄ are hydrogen ormethoxy; n is the integer 1 or 2; and the acid addition salts thereofprepared from pharmaceutically acceptable acids.

Acids useful for preparing the acid addition salts of the inventioninclude inorganic acids such as hydrochloric hydrobramic, sulfuric,nitric, phosphoric and perchloric acids, as well as organic acids suchas tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.

The compounds of the invention are prepared by either of the twosequences of reactions described below wherein R, R₁, R₂, R₃, R₄ and nare as defined earlier. The starting compounds, the4-benzoyl-piperidines, are prepared from N-acetylisonipecotic acid orfrom 1-acetylisonipecotamide by the methods described by Robert L.Duncan, Jr. et al., J. Med. Chem. l, 1, (1970).

The 4-(hydroxybenzoyl)piperidines are prepared by a somewhat differentmethod. The N-acetylisonipecotic acid chloride is reacted with an alkoxysubstituted benzene under Friedel-Crafts condition to give a1-acetyl-4-(alkoxybenzoyl)piperidine. The reaction of this piperidinewith hydrogen bromide produces hydrolysis of the acetyl group anddealkylation of the alkoxy group, giving a corresponding4-(hydroxybenzoyl)piperidine.

Additionally, a benzoylpiperidine can be prepared by the three stepmethod outlined below.

1. A 4-benzoyl-1-methylpiperidine is produced by the reaction of abenzonitrile of the formula ##STR2## with a Grignard reagent preparedfrom N-methyl-4-chloropiperidine at a temperature of from 15° C. to theboiling point of the solvent, if any, for from 1 to 15 hours. Onepreferred method utilizes tetrahydrofuran as the solvent and allows themixture to react at reflux for 2 hours and then at ambient temperatureovernight.

2. The reaction of an above piperidine with a substituted chloroformatesuch as phenylchloroformate or an alkylchloroformate in the presence ofan organic solvent such as methylene chloride or toluene at atemperature of from ambient to the boiling point of the solvent for froma few minutes to 12 hours produces N-carbonyl compound of the formula##STR3## wherein Y is phenyl or alkyl. A preferred chloroformate isphenylchloroformate.

3. A benzoylpiperidine is prepared by cleaving the carbonyl moiety fromthe above N-carbonyl compound. A preferred method of cleaving is carriedout by dissolving an N-carbonyl compound in an aqueous solution of30-50% potassium hydroxide and an organic solvent such as ethanol andpermitting the solution to react at a temperature of from ambient to theboiling point of the solvent for from 1 hour to 60 hours.

METHOD I

A. A sample of 3-(ω-bromoalkyl)indole is reacted with a4-benzoylpiperidine of the formula ##STR4## in the presence of asuitable organic solvent such as dimethylformamide, n-butanol, ordimethylsulfoxide, with or without an acid scavenger such as potassiumcarbonate, triethylamine or sodium bicarbonate, at a temperature of fromabout 20° C. to the boiling point of the solvent for from 30 minutes to120 hours to give a compound of the invention of the formula ##STR5##

B. These benzoylpiperidylalkylinodoles can be reduced to give a compoundof the invention of the formula ##STR6## In one preferred method, sodiumborohydride is utilized as the reducing agent.

METHOD II

A. A sample of an indole of the formula ##STR7## in a solvent such asanhydrous ether is allowed to react with oxalyl chloride at atemperature of from -15° to 15° C for from a couple of minutes to onehour to produce a mixture of a corresponding 3-indoleglyoxyloyl chloridein the solvent which is then added to a cooled solution of4-benzoylpiperidine in a suitable organic solvent such as chloroformoptionally containing an acid scavenger such as potassium carbonate andallowing the mixture to react at a temperature of from 15° to 40° C. fora few minutes to 12 hours to produce a4-benzoyl-1-(indol-3-ylglyoxyloyl)piperidine of the formula ##STR8##

B. An above (indol-3-ylglyoxyloyl)piperidine is reduced to produce anarylhydroxymethylpiperidylethylindole a compound of the invention of theformula illustrated in Method I, step B in which n is 1. A preferredmethod utilizes lithium aluminum hydride as the reducing agent,tetrahydrofuran as a solvent, the boiling point of the solvent as thereaction temperature and a reaction time of from a few minutes to 5hours.

The compounds of the invention are useful as tranquilizers due to theirdepressant action on the central nervous system of mammals. Thisactivity is demonstrated in the mouse observation procedure, a standardassay for central nervous system depressants [Psychopharmacologia, 9,259 (1966). Thus, for example, the minimum effective dose (MED) at which3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl} indole hydrochloride displayssignificant effects on behavior and reflex depression together withmuscle relaxation is 1 mg/kg of body weight. Similarly, MED'S of othercompounds are:

    ______________________________________                                                                   MED                                                Compound                   mg/kg                                              ______________________________________                                        3-{2-[4-(4-fluorobenzoyl)piperidyl]ethyl}-                                                               10                                                 indole                                                                        3-[2-(4-benzoylpiperidyl)ethyl]indole                                                                    20                                                 3-{2-[4-(4-toluyl)piperidyl]ethyl}indole                                                                 40                                                 ______________________________________                                    

Some compounds of the invention are also useful as anti-hypertensiveagents due to their ability to depress blood pressure in mammals.Anti-hypertensive activity is measured in the spontaneous hypertensiverate by the indirect tail cuff method described in A. Schwartz, Ed.,Methods in Pharmacology, Vol. I, page 135, Appleton-Century-Crofts, NewYork, New York 1971. In this procedure a group of five animals are dosedorally with 100 mg of the compound per kg. of body weight in relation toa control group of the same number. The antihypertensive activity inthis test of some of the compounds of the invention is illustrated inTable I.

                  TABLE I                                                         ______________________________________                                                                 Day 1   Day 3                                        Compound                 mmHg    mmHg                                         ______________________________________                                        3-[2-(4-benzoylpiperidyl)ethyl]indole                                                                  -53.8   -79.7                                        3-{2-[4-(4-toluyl)piperidyl]ethyl}indole                                                               -63.6   -61.0                                        3-{2-[4-(4-chlorobenzoyl)piperidyl]ethyl}indole                                                        -39.0   -67.8                                        3-{2-[4-(4-bromobenzoyl)piperidyl]ethyl}indole                                                         -15.8   -57.2                                        ______________________________________                                    

Compounds of the invention are useful as analgesic agents due to theirability to alleviate pain in mammals. The activity of the compounds isdemonstrated in the 2-phenyl-1,4-benzoquinone-induced writhing test inmice, a standard assay for analgesia [Proc. Soc. Exptl. Biol. Med., 95,79 (1975)]. For example at doses of 4.4, 11, 15, 20 and 35 mg/kg of bodyweight, 3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl}indole hydrochloride,3-{2-[4-(4-toluyl)piperidyl]-ethyl}indole,3-{2-[4-(4-fluorobenzoyl)piperidyl]ethyl}indole hydrochloride,3-[2-(4-benzoylpiperidyl)ethyl]indole, and3-{2-[4-(4-chlorobenzoyl)piperidine]ethyl}indole, respectively, exhibitan approximately 50% inhibition of writhing.

The above date illustrates that the compounds of the present inventionare useful as tranquilizers and for the treatment of hypertension andalleviation of pain when administered to mammals at doses of from 0.1 to100 mg/kg. Examples of the compounds of the invention are:

3-{2-[4-(4-hydroxybenzoyl)piperidyl]ethyl}indole;

3-{2-[4-(4-ethylbenzoyl)piperidyl]ethyl}indole;

3-{2-[4-(4-n-butylbenzoyl)piperidyl]ethyl}indole;

3-{2-[4-(4ethoxybenzoyl)piperidyl]ethyl}indole;

3-{2-[4-(4-trifluoromethylbenzoyl)piperidyl]ethyl}indole;

3-{2-[4-(2-bromo-4-ethylbenzoyl)piperidyl]ethyl}indole;

3-{-[4-(3,4-dichlorobenzoyl)piperidyl]ethyl}indole;

3-{2-[4-(4-chlorophenylhydroxymethyl)piperidyl]ethyl}indole;

3-{2-[4-(4-isopropylphenylhydroxymethyl)piperidyl]ethyl}indole;

5-methoxy-3-{3-[4-(3-methoxybenzoyl)piperidyl]propyl}indole; and

5,6-dimethoxy-2-methyl-3-{3-[4-(4-trifluoromethylphenylhydroxymethyl)piperidyl]propyl}indole.

The compounds of the present invention may be administered to a patientby a convenient route such as orally, intramuscularly, intraveneously,subcutaneously or intraperitoneally. The preferred route ofadministration is oral, for example, with an inert diluent or with anedible carrier or in gelatin capsules or tablets.

For the purpose of oral therapeutic administration, the active compoundsof this invention may be incorporated with excipients and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gum, and the like. These preparations should contain aleast 0.5% of active compound, but may be varied depending upon theparticular form and may conveniently be between 7% to about 70% byweight of the unit. The amount of active compound in such compositionsis such that a suitable dosage will be obtained. Preferred compositionsand preparations according to the present invention are prepared so thatan oral dosage unit form contains between 1 and 200 milligrams of activecompound.

The tablets, pills, capsules, troches, and the like may also contain thefollowing ingredients: a binder such as gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, potato starch and the like; a lubricant such as magnesiumstearate; and a sweetening agent such as sucrose or saccharin may beadded or a flavoring agent such as pippermint, methyl salicylate, ororange flavoring. When the dosage unit form is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or both. A syrup may contain, in addition to the activecompounds sucrose as a sweetening agent, and certain preservatives, dyesand colorings, and flavors. Materials used in preparing these variouscompositions must be pharmaceutically pure and non-toxic in the amountsutilized.

For the purpose of parenteral therapeutics administration, the activecompounds of the invention may be incorporated into a solution ofsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied to be between 0.5 and about 30% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will beobtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

The invention is further illustrated by the following examples, givenfor illustrative purposes.

EXAMPLE I

A. A solution of 51.6 g of isonipecotic acid in 200 ml of aceticanhydride is refluxed for 2 hours and allowed to stir at ambienttemperature for 16 hours. The solution is concentrated and the resultingresidue is triturated in ether. The solid is collected by filtration andrecrystallized from an isopropyl alcohol-diisopropyl ether mixturegiving 1-acetylisonipecotic acid as a white solid.

B. A sample of 65.4 g of 1-acetylisonipecotic acid is dissolved in 400ml of thionyl chloride. The acid chloride precipitates from solution andone liter of petroleum ether is added. The mixture is filtered, thesolid residue is washed several times with petroleum ether and dried,giving 1-acetylisonipecotoyl chloride as a white solid.

C. 70 g of 1-acetylisonipecotoyl chloride are slowly added to a stirringmixture of 93.0 g of aluminum chloride in 150 ml of fluorobenzene. Aftertotal addition, the mixture is refluxed for one hour. The mixture ispoured onto ice and the two resulting layers separate. The aqueous layeris extracted twice with chloroform and the extracts are added to thefluorobenzene which separated previously. The organic solution is driedand concentrated under reduced pressure leaving a crystalline whitesolid. The solid is recrystallized from a ligroindiisopropyl ethermixture, producing 1-acetyl-4-(4-fluorobenzoyl)piperidine.

D. A solution of 70.6 g of 1-acetyl-4-(4-fluorobenzoyl)piperidine in 200ml of 6N HCl is refluxed for 2 hours. The cooled solution is extractedtwice with ether, the aqueous solution basified with sodium hydroxideand then extracted with benzene. The benzene extracts are dried,filtered and the filtrate is concentrated under reduced pressure. Theresidual oil is dissolved in ether and HCl gas is bubbled into thesolution with stirring. The salt is collected by filtration, washed withether and dried. The salt is recrystallized from isopropanol to give thesolid product of 4-(4-fluorobenzoyl)piperidine hydrochloride, mp222°-224° C.

E. A stirred mixture of 10.1g of 3-(2-bromoethyl)indole, 15.2 g of4-(4-fluorobenzoyl)piperidine, and 15.0 g of anhydrous potassiumcarbonate in 150 ml of n-butanol is refluxed under nitrogen for threehours. The mixture is cooled, filtered, and ether is slowly added to thefiltrate to precipitate a white solid, the starting piperidine, which isremoved by filtration. The solvent is removed under reduced pressure,leaving a soft orange solid. The solid is dissolved in absolute ethanol,the solution is cooled, and HCl gas is bubbled into the solution. Afterstanding about 5 minutes, the salt precipitates as off-white needles.The needles are recrystallized from a methanol-ether mixture to giveslightly off-white needles, mp 267°-269° C. (dec.) of3-{2-[4-(4fluorobenzoyl)piperidyl]ethyl}indole hydrochloride

Analysis: Calculated for C₂₂ H₂₃ FN₂ O·HCl: 68.29%, C; 6.25%, H; 7.24%,N; Found: 68.08%, C; 6.49-trifluoromethylbenzoyl)piperidine H; 7.32%, N.

By following the manipulative procedure of step E,3-{2-[4-(3-trifluoromethyl)piperidyl]ethyl}indole is prepared bysubstituting 4-(3-trifluoromethylbenzoyl)piperidine for4-(4fluorobenzoyl)piperidine.

4-(3-trifluoromethylbenzoyl)piperidine is prepared in the followingmanner: A solution of 102.5 g of 3-bromobenzotrifluoride in 25 ml ofether is added dropwise to a stirring mixture of 11.5 g of magnesiumturnings in 300 ml of anhydrous ether to maintain a moderate reflux.After total addition the resulting dark mixture is stirred for 1 hour atambient temperature. A solution of 60.0 g of 1-acetyl-4-cyanopiperidinein 100 ml of tetrahydrofuran is slowly added to this mixture and themixture is stirred for 16 hours. An excess of an aqueous solution ofammonium chloride is added and the mixture is heated on a steam bath for3 hours. The mixture is allowed to cool, extracted with benzene and thecombined extracts are dried. The solvent is removed and the residue isdissolved in ethanol and basified with sodium hydroxide. The alkalinesolution is refluxed for 3 hours, cooled and extracted with benzene. Thecombined benzene extracts are dried and the benzene is removed, leavingthe oil, 4-(3 -trifluoromethylbenzoyl)piperidine, which is converted tothe hydrochloride, mp 196°-198° C.

EXAMPLE 2

A suspension of 2.8 g of 3-{2-[4(4-fluorobenzoyl)piperidyl]ethyl}indole,free base of Example 1(e), in 180 ml of isopropanol is added dropwise toa stirred mixture of 102 g of sodium borohydride in 75 ml of isopropanolat 5° C. After total addition, the mixture is permitted to reach ambienttemperature, and is stirred for 4.5 hours. The solution is poured intowater, the aqueous solution is extracted with methylene chloride, theorganic layer is dried, and the solvent is removed under reducedpressure to give a yellow oil. The oil is stirred vigorously in thepresence of hexane, and is crystallized to a white solid. The solid isrecrystallized from acetonitrile and then from an ethanol-water mixtureto give a white powder, mp 188°-190° C., of3-{2-[4-(4-fluorophenylhydroxymethyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₂ H₂₅ FN₂ O: 74.96%, C; 7.15%, H; 7.95%, N;5.39%, F. Found: 74.85%, C; 7.22%, H; 8.02%, N; 5.05%, F.

EXAMPLE 3

A. By following the manipulative procedures described above in Example1(c), and (d), 37.4 g of 1-acetylisonipecotoyl chloride, [Example 1(b)]and 40 g of aluminum chloride in 90 ml of chlorobenzene are reacted toproduce 4-(4-chlorobenzoyl)piperidine hydrochloride. The salt isrecrystallized thrice from an ethanol-ether mixture to give a whiteproduct, mp. 233°-235° C.

B. A solution of 13.0 g of 4-(4-chlorobenzoyl)piperidine hydrochloride,10.7 g of triethylamine and 9.8 g of 3-(2-bromoethyl)indole in 350 ml ofdimethylformamide is stirred at ambient temperature for 42 hours. Wateris added dropwise to the solution to precipitate a pale yellow solid.The solid is collected, washed with water and dried. The solid isrecrystallized from isopropanol to give off white flakes, mp 174°-176°C., of 3-{2-[4-(4-chlorobenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₂ H₂₃ ClN₂ O: 72.01%, C; 6.31%, H; 7.63%, N;9.66%, Cl; Found: 72.14%, C; 6.26%, H; 7.51%, N; 9.76%, Cl.

EXAMPLE 4

A. 32.0 g of 1-acetylisonipecotoyl chloride, Example 1(b) are addedportionwise to a stirred mixture of 45.3 g of aluminum chloride, 28.3 gof bromobenzene and 120 ml of ethylene dichloride. The solution isstirred overnight, poured onto ice, the organic phase is collected, andthe aqueous layer is extracted with chloroform. The organic solutionsare combined, dried, and the solvent is removed under reduced pressureto give a yellow oil which crystallizes to a soft solid. The solid istriturated with ether, collected and dried to give1-acetyl-4-(4-bromobenzoyl)piperidine.

B. A sample of 30.9 g of 1-acetyl-4-(4-bromobenzoyl)piperidine isrefluxed for 6 hours in 6N HCl, cooled, and the resulting insoluble saltis collected. The salt is recrystallized from an ethanol-ether mixture,then from isopropanol to give off-white crystals, mp 225°-227° C.,4-(4-bromobenzoyl)piperidine hydrochloride.

C. A sample of 14.6 g of 4-(4-bromobenzoyl)piperidine hydrochloride istreated according to the manipulative procedure described above inExample 3(b) to produce a yellow solid. The solid is recrystallized from95% ethanol (charcoal treatment) and then from a toluenecyclohexanemixture to give an off-white solid, mp 178°-180° C.,3-{2-[4-(4-bromobenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₂ H₂₃ BrN₂ O: 64.23%, C; 5.64%, H; 6.81%, N;19.43%, Br; Found: 64.08%, C; 5.55%, H; 6.61%, N; 19.34%, Br.

EXAMPLE 5

A. By following the manipulative procedures described above in Examples1(c) and (d), 1-acetylisonipecotoyl chloride, Example 1(b), toluene, andaluminum chloride are reacted to produce 4-(4-toluyl)piperidinehydrochloride. The salt is recrystallized thrice from a methanol-ethermixture (one charcoal treatment) to give colorless needles, mp 275°-277°C., (dec.).

B. By following the manipulative procedure described above in Example3(b), 11.2 g of 4-(4-toluyl)piperidine, 6.1 g of triethylamine and 11.2g of 3-(2-bromoethyl)indole are treated to produce a white solid. Thesolid is recrystallized from 95% ethanol (charcoal treatment) to givewhite flakes, mp 157.5°-159° C., of3-{2-[4-(4toluoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₃ H₂₆ N₂ O: 79.72%, C; 7.56%, H; 8.08%, N.Found: 79.69%, C; 7.55%, H; 8.02%, N.

EXAMPLE 6

A. By following the manipulative procedure described above in Example4(a), 32.0 g of 1-acetylisonipecotoyl chloride, [Example 1(b)] are addedto a stirring solution of 30.6 g of diphenylether and 45.3 g of aluminumchloride in 100 ml of ethylene dichloride to produce a yellow oil of1-acetyl-4-(4-phenoxybenzoyl)piperidine.

B. A sample of 48.8 g of 1-acetyl-4-(4-phenoxybenzoyl)piperidine isrefluxed for 6 hours in 6N HCl. Upon cooling a white solid precipitatesfrom solution, is collected, washed with water, then acetone, and dried.The filtrate is extracted with ether, the aqueous phase is basified withsodium hydroxide and extracted with benzene. The benzene is dried, andthe solvent is removed under reduced pressure to give a solid which isconverted to a hydrochloride. The salt is recrystallized from anethanol-ether mixture to give a white solid, mp 219°-220° C.,4-(4-phenoxybenzoyl)piperidine hydrochloride.

C. A solution of 10.3 g of 3-(2-bromoethyl)indole, 14.5 g4-(4-phenoxybenzoyl)piperidine hydrochloride and 10 g of triethylaminein 350 ml of dimethylformamide is treated according to the manipulativeprocedure described above in Example 3(b) to produce a yellow solid. Thesolid is recrystallized thrice from a benzene-hexane mixture (onecharcoal treatment) to give a pale yellow crystalline material, mp 180°C., of 3-{2-[4-(4-phenoxybenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₈ H₂₈ N₂ O₂ : 79.22%, C; 6.65%, H; 6.60%, N;Found: 79.07%, C; 6.56%, H; 6.52%, N.

EXAMPLE 7

A. A sample of anisole is treated according to the manipulativeprocedures described above in Example 1(c) and (d) to produce4-(4-methoxybenzoyl)piperidine hydrochloride which, when recrystallizedfrom isopropanol, had a mp of 251°-256° C.

B. A solution of 11.4 g of 4-(4-methoxybenzoyl)-piperidine, 10.1 g of3-(2-bromoethyl)indole and 5.6 g of triethylamine in 500 ml ofdimethylformamide is treated according to the manipulative proceduredescribed above in Example 3(b) to produce a white solid. The solid isrecrystallized twice from 95% ethanol (one charcoal treatment) to givesilver-white flakes, mp 175°-177° C., of3-{2-[4-(4-methoxybenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₃ H₂₆ N₂ O₂ : 76.20%, C; 7.23%, H; 7.73%, N;Found: 76.27%, C; 7.32%, H; 7.83%, N.

EXAMPLE 8

A. A sample of 18.0 g of 1acetyl-4-(4-methoxybenzoyl)piperidine, theintermediate of Example 7(a), is refluxed with 300 ml of 48% hydrogenbromide under nitrogen for 4 hours. The solution is permitted to standfor 16 hours at 5° C., causing a white solid to precipitate. The solidis collected, washed well with acetone and dried. Recrystallization frommethanol gives colorless needles, mp 273°-275° C., of4-(4hydroxybenzoyl)piperidine hydrobromide.

B. A mixture of 9.7 g of 4-(4-hydroxybenzoyl)piperidine hydrobromide,6.4 g of sodium bicarbonate and 7.0 g of 3-(2-bromoethyl)indole in 90 mlof dimethylsulfoxide is stirred overnight under nitrogen at 50° C. Aftercooling to ambient temperature, water is added dropwise, precipitating agummy brown solid. The supernatant solution is decanted from the solid,triturated with water, collected, and dried. Recrystallization from anethanol-water mixture gives an off-white solid, mp 212°-214° C. (dec.)of 3-{2-[4-(4-hydroxybenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₂ H₂₄ N₂ O₂ : 75.83%, C; 6.94%, H; 8.04%, N;Found: 75.61%, C; 6.85%, H; 7.90%, N.

EXAMPLE 9

A. A sample of benzene is treated according to the manipulativeprocedures described above in Examples 1(c) and (d) to produce4-(benzoyl)piperidine hydrochloride. The salt is recrystallized fromisopropanol to give a mp of 223°-225° C.

B. A solution of 10.4 g of 4-(benzoyl)piperidine, 6.1 g of triethylamineand 11.2 g of 3-(2-bromoethyl)indole in 350 ml of dimethylformamide isstirred at ambient temperature for 16 hours. Water is added dropwise,precipitating an off-white solid. The solid is collected, washed withwater and low boiling petroleum ether, and dried. The solid isrecrystallized from 95% ethanol to give white flakes, mp 145°-147° C.,of 3-[2-(4-benzoylpiperidyl)ethyl]indole.

Analysis: Calculated for C₂₂ H₂₄ N₂ O: 79.48%, C; 7.28%, H; 8.43%, N;Found: 79.51%, C; 7.33H; 8.49%, N.

EXAMPLE 10

A. By following the manipulative procedure described above in Example4(a), 25 g of 1-acetylisonipecotoyl chloride are added to stirredsuspension of 25 g of aluminum chloride and 14 g of m-fluorotoluene in220 ml of ethylene dichloride to produce the oil,1-acetyl-4-(2-fluoro-4methylbenzoyl)piperidine.

B. A sample of 17.1 g of 1-acetyl-4-(2-fluoro-4-methylbenzoyl)piperidineis refluxed in 200 ml of 6N HCl for 24 hours and then stirred for anadditional 6 hours at ambient temperature. The solution is extractedwith ether, the aqueous layer is basified with 6N NaOH, extracted withbenzene, dried and the solvent is removed under reduced pressure,leaving a yellow oil. The oil is added to ethereal hydrogen chloride andthe resulting precipitate is collected, washed well with ether anddried. The solid is recrystallized from a methanol-ether mixture to givethe final solid product, mp 220°-221° C. of4-(2-fluoro-4-methylbenzoyl)piperidine hydrochloride.

C. A solution of 15.5 g of 3-(2-bromoethyl)indole, 17.5 g of4-(2-fluoro-4-methylbenzoyl)piperidine hydrochloride and 19 g oftriethylamine in 500 ml of dimethylformamide is stirred at ambienttemperature for 64 hours. Water is added dropwise, resulting in aprecipitate. The precipitate is collected by filtration, washed wellwith water and dried. The solid is recrystallized from a methanol-ethermixture and from a benzene-hexane mixture to give off-white flakes, mp117°-118° C., of3-{2-[4-(2-fluoro-4-methylbenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₃ H₂₅ FNO₂ : 75.79%, C; 6.92%, H; 5.21%, F;7.69%, N; Found: 75.96%, C; 7.07%, H; 5.15%, F; 7.57%, N.

EXAMPLE 11

A. A sample of o-xylene is treated according to the manipulativeprocedures described above in Example 1(c) to give1-acetyl-4-(3,4-dimethylbenzoyl)piperidine.

B. A sample of 21.3 g of 1-acetyl-4-(3,4-dimethylbenzoyl)piperidine isrefluxed in 100 ml 95% ethanol and 100 ml 35% potassium hydroxide for 6hours and then allowed to stir at ambient temperature overnight. Theaqueous layer is extracted with benzene, the organic extracts arecombined and dried. The solvent is removed under reduced pressureleaving a yellow oil. The oil is dissolved in ether and hydrogenchloride is bubbled into the solution. The resulting solid precipitateis collected, washed well with ether and dried. The solid isrecrystallized thrice from an isopropanol-ether mixture to give thesalt, mp 258°-259° C., 4-(3,4-dimethylbenzoyl)piperidine hydrochloride.

C. A solution of 9.6 g of 3-(2-bromoethyl)indole, 11.5 g of4-(3,4-dimethylbenzoyl)piperidine hydrochloride and 10.1 g oftriethylamine in 300 ml of dimethylformamide is treated according to themanipulative procedure described in Example 3(b) to give an indole,which is purified on a silica gel column, eluted with a 5%methanol-benzene mixture and recrystallized from an ethanol-watermixture to give the solid, mp 172°-173° C.,3-{2-[4-(3,4-dimethylbenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₄ H₂₈ N₂ O: 79.69%, C; 7.83%, H; 7.77%, N;Found: 79.95%, C; 7.90%, H; 7.71%, N.

EXAMPLE 12

A. 19.1 g of 1acetylisonipecotoyl chloride, Example 1(b) are addedportionwise to a stirring suspension of 13 g of t-butylbenzene and 27 gof aluminum chloride in 175 ml of dichloroethane. The reaction mixtureis refluxed for 1 hour, cooled, and poured onto ice. The organic layeris separated and the aqueous layer is extracted with chloroform. Theorganic layers are combined, dried, and the solvent is removed underreduced pressure leaving the oil,1-acetyl-4-(4-t-butylbenzoyl)piperidine.

B. A sample of 27.6 g of 1-acetyl-4-(4-t-butylbenzoyl)piperidine isrefluxed in 100 ml of ethanol and 100 ml of 35% aqueous potassiumhydroxide for 6 hours, and then allowed to stir at ambient temperaturefor 62 hours. The solution is extracted with benzene, the benzeneextracts are dried, and the benzene is removed under reduced pressureleaving an oil. The oil is dissolved in ether and hydrogen chloride gasis bubbled into the solution. The resulting beige precipitate iscollected and dried. The precipitate is recrystallized from 2-butanoneto give the solid, mp 230°-231° C., 4-(4t-butylbenzoyl)piperidinehydrochloride.

C. A solution of 9.4 g of 3-(2bromoethyl)indole, 11.7 g of4-(4-t-butylbenzoyl)piperidine hydrochloride and 9 g of triethylamine in350 ml of dimethylformamide is treated according to the manipulativeprocedure described in Example 3(b) to produce a yellow solid. The solidis recrystallized from a methanol-water mixture (charcoal treatment)then twice from a benzene-hexane mixture to give the off-white indole,mp 173°-174° C., 3{2-[4-(4-t-butylbenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C.sub. 26 H₃₂ N₂ O: 80.37%, C; 8.30%, H; 7.21%,N; Found: 80.15%, C; 8.47%, H; 7.07%, N.

EXAMPLE 13

A. 16.5 g of 1-acetylisonipecotoyl chloride, Example 1(b) are slowlyadded to a stirring mixture of 60 ml of m-dimethoxybenzene and 20.0 g ofaluminum chloride. Stirring is continued for 1 hour at ambienttemperature and then for an additional 1 hour at about 100° C. Thereaction mixture is allowed to cool to ambient temperature, poured intoice-water, and extracted with chloroform. The combined extracts aredried and the chloroform is removed leaving a yellow oil. The oil istriturated with hexane to effect a white solid which is collected anddried. Recrystallization from ethyl acetate yields colorless needles, mp138°-140° C., 1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine.

Analysis: Calculated for C₁₅ H₁₉ NO₄ : 64.96%, C; 6.90%, H; 5.05%, N;Found: 65.05%, C; 6.98%, H; 4.92%, N.

B. A sample of 1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine istreated according to the manipulative procedure described above inExample 1(d) to give 4-(2-hydroxy-4-methoxybenzoyl)piperidine.

C. A mixture of 4.0 g of 4-(2-hydroxy-4-methoxybenzoyl)piperidine, 3.3 gof 3-(2-bromoethyl)indole and 1.4 g of sodium bicarbonate in 60 ml ofdimethylsulfoxide is stirred at ambient temperature for 42 hours and at60° C. for an additional 6 hours. The reaction mixture is allowed tocool to ambient temperature and water is added dropwise to produce agummy, brown precipitate. The precipitate is collected and trituratedwith ethanol to give a white solid which is recrystallized twice fromethanol (one charcoal treatment) to give silver-white flakes, mp150°-152° C., 3{2-[4-(2-hydroxy-4-methoxybenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₃ H₂₆ N₂ O₃ : 72.99%, C; 6.92%, H; 7.40%, N;Found: 73.23%, C; 6.92%, H; 7.32%, N.

EXAMPLE 14

A. 18.7 g of 1acetylisonipecotoyl chloride, Example 1(b) are addedslowly to a stirred mixture of 40.0 g of m-dimethoxybenzene and 19.2 gof aluminum chloride in 75 ml of carbon disulfide. The reaction mixtureis stirred at ambient temperature for an hour, poured into ice-water andextracted with chloroform, the combined extracts are dried and thechloroform is removed, leaving a yellow oil. The oil is triturated withether to give a white solid, which is recrystallized twice from ethylacetate to give the pure solid, mp 132°-134° C.,1-acetyl-4-(2,4-dimethoxybenzoyl)piperidine.

Analysis: Calculated for C₁₆ H₂₁ NO₄ : 65.95%, C; 7.26%, H; 4.80%, N;Found: 65.86%, C; 7.30%, H; 4.63%, N.

B. By following the manipulative procedure described above in Example1(b), 7.4 g of 1-acetyl-4-(2,4-dimethoxybenzoyl)piperidine in 250 ml of6N HCl are treated to give a hydrogen chloride salt which isrecrystallized once from an ethanol-ether mixture and twice from ethanolto give the compound, mp 198°-200° C.,4-(2,4-dimethoxybenzoyl)piperidine hydrochloride.

Analysis: Calculated for C₁₄ H₁₉ NO₃ ·HCl: 58.84%, C; 7.05%, H; 4.90%,N; 12.41%, Cl; Found: 58.97%, C; 7.02%, H; 5.11%, N; 12.54%, Cl.

C. To a stirring solution of 8.0 g of 4-(2,4-dimethoxybenzoyl)piperidinehydrochloride and 6 ml of triethylamine in 250 ml of dimethylformamideis added a solution of 6.4 g of 3-(2-bromoethyl)indole in 50 ml ofdimethylformamide. The reaction mixture is permitted to stir at ambienttemperature for 72 hours and then 500 ml of water is added dropwise andextracted with chloroform. The combined extracts are dried and most ofthe chloroform removed leaving a dark oil. The oil is subjected tocolumn chromatography on a silica gel column and eluting with a 3%methanol in chloroform solution to give3-{2-[4-(2,4-dimethoxybenzoyl)piperidyl]ethyl}indole. The indole isrecrystallized thrice from an ethanol-water mixture to give the pureindole, mp 110°-112° C.

Analysis: Calculated for C₂₄ H₂₈ N₂ O₃ : 73.44%, C; 7.19%, H; 7.14%, N;Found: 73.42%, C; 7.31%, H; 7.18%, N.

EXAMPLE 15

A. A few drops of ethyl bromide are added to a stirring suspension,under nitrogen, of 3.2 g of magnesium turnings in 10 ml oftetrahydrofuran. After a reaction begins, 17.7 g ofN-methyl-4-chloropiperidine in 50 ml of tetrahydrofuran are addeddropwise while maintaining a moderate reflux. After total addition, thereaction mixture is heated at reflux for 1 hour and 15.2 g of3-tolylnitrile in 10 ml of tetrahydrofuran are slowly added. After thisaddition is complete the reaction mixture is heated at reflux for anadditional 2 hours and then permitted to stir at ambient temperature for16 hours. The reaction mixture is poured into a solution of 35 g ofammonium chloride in 500 ml of ice-water and heated on a steam bath for3 hours, cooled and extracted with benzene. The combined benzeneextracts are dried and most of the benzene is removed, leaving theorange oil. The oil is dissolved in ether and the oxalate salt isprepared by the addition of a solution of anhydrous oxalic acid inisopropanol. The white oxalate salt is recrystallized twice from ethanolto give the product, mp 183°-185° C., 1-methyl-4-(3-toluyl)piperidineoxalate.

Analysis: Calculated for C₁₄ H₁₉ N·(CO₂ H)₂ : 62.53%, C; 6.89%, H;4.55%, N; Found: 62.32%, C; 7.01%, H; 4.52%, N.

B. 18.8 g of phenylchloroformate are added dropwise to a solution of21.3 g of 1-methyl-4-(3toluyl)piperidine. free base of the above, in 100ml of methylene chloride and the reaction mixture is stirred at ambienttemperature for 16 hours and the solvent removed leaving a dark brownsemisolid. The semisolid is suspended in 500 ml of 1N hydrogen chloridesolution and extracted with ether. Some of the desired materialprecipitates from the aqueous phase and is collected. The ether extractis dried and the ether removed under reduced pressure to give a brownsolid, which is stirred in a 50% methanol- 2% aqueous potassiumcarbonate solution at ambient temperature for 16 hours. Filtration ofthe mixture provides more of the desired product. The combined productis recrystallized twice from an ethanol-water mixture to give thecompound, 1-phenoxycarbonyl-4-(3-toluyl)piperidine, mp 127°-130° C.

Analysis: Calculated for C₁₂ H₂₁ NO₃ : 74.28%, C; 6.54%, H; 4.33%, N;Found: 74.35%, C; 6.62%, H; 4.29%, N.

C. A solution of 11.9 g of 1-phenoxycarbonyl-4-(3-toluyl)piperidine and75 ml of an aqueous 50% potassium hydroxide solution in 300 ml ofethanol is heated at reflux for 24 hours and then stirred at ambienttemperature for an additional 36 hours. 100 ml of water are added, theethanol is partially removed, the resulting mixture is extracted withether and the combined ether extracts are extracted with 1N HCl. Theaqueous solution is basified with an aqueous sodium hydroxide solution,extracted with ether, the combined ether extracts are dried, and theether is removed, leaving a dark oil. The oil is dissolved in ether andethereal hydrogen chloride is added to produce the sale which iscollected by filtration, dried and recrystallized thrice from anethanol-water mixture to give 4-(3-toluyl)piperidine hydrochloride, mp196°-197° C.,

Analysis: Calculated for C₁₃ H₁₇ NOHCl: 65.13%, C; 7.57%, H; 5.83%, N;14.79%, Cl; Found: 64.90%, C; 7.59%, H; 5.73%, N; 14.65%, Cl.

D. 4.2 g of potassium carbonate are added to a stirred solution of 3.8 gof 4-(3-toluyl)piperidine hydrochloride in 400 ml of dimethylformamide.The mixture is stirred at ambient temperature for 1 hour and then asolution of 3.4 g of 3-(2-bromoethyl)indole in 100 ml ofdimethylformamide is introduced. The resulting mixture is stirred atambient temperature for 120 hours, filtered and 1.5 l of water addeddropwise to effect a precipitate. The precipitate is collected andrecrystallized thrice from ethanol (one charcoal treatment), to give theindole, mp 171°-173° C., 3-{2-[4-(3-toluyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₃ H₂₆ N₂ O: 79.93%, C; 7.56%, H; 8.09%, N.Found: 79.85%, C; 7.71%, H; 8.17%, N.

EXAMPLE 16

A. By following the manipulative procedure outlined in Example 15(a), asample of 2-fluorobenzonitrile is treated to produce a hydrochloridesalt which is recrystallized twice from an ethanol-ether mixture to giveoff-white crystals, mp 167°-169° C.,4-(2-fluorobenzoyl)-1-methylpiperidine hydrochloride.

Analysis: Calculated for C₁₃ H₁₆ FNO·CHl: 60.58%, C; 6.65%, H; 5.43%, N;7.37%, F; Found: 60.30%, C; 6.78%, H; 5.43%, N; 7.59%, F.

B. 47.0 g of phenylchloroformate are added to a stirring solution of57.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine in 750 ml of toluene.The reaction mixture is refluxed for 5 hours, cooled to ambienttemperature, filtered, and the solvent is removed leaving a lightcolored oil. The oil is triturated with hexane to give a crystallinematerial which is recrystallized twice from an ethanol-water mixture andonce from ethanol to give the compound, mp 95°-96° C.,1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine.

Analysis: Calculated for C₁₉ H₁₈ FNO₃ : 69.71%, C; 5.54%, H; 4.28%, N;5.81%, F. Found: 69.45%, C; 5.67%, H; 4.13%, N; 6.10%, F.

C. A solution of 40.5 g of1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine in 500 ml of ethanol and500 ml of an aqueous 30% potassium hydroxide solution is stirred at atemperature slightly below reflux for 16 hours, allowed to cool toambient temperature, diluted with water, and the ethanol is partiallyremoved under reduced pressure. The resulting aqueous suspension isextracted with ether, the combined ether extracts are extracted with 1Nhydrogen chloride and the aqueous acid solution is basified with anaqueous sodium hydroxide solution. The basic solution is extracted withether, the combined ether extracts are dried and the ether is removedunder reduced pressure leaving a dark oil. The oil is dissolved in aminimum amount of ethanol and ethereal-hydrogen chloride is addeddropwise to effect a precipitate. The precipitate is collected byfiltration, dried and recrystallized twice from an ethanol-ether mixtureto give a white solid, mp 185°-187° C., 4-(2-fluorobenzoyl)piperidinehydrochloride.

Analysis: Calculated for C₁₂ H₁₄ FNO·HCl 59.14%, C; 6.20%, H; 5.74%, N;7.80%, F; Found: 58.90%, C; 6.36%, H; 5.50%, N; 7.56%, F.

D. A solution of 9.1 g of 3-(2-bromoethyl)indole in 100 ml ofdimethylformamide is added to a stirring solution of 11.2 g of4-(2-fluorobenzoyl)piperidine hydrochloride and 13 g of potassiumcarbonate in 400 ml of dimethylformamide. The reaction mixture isstirred at ambient temperature for 24 hours, and then 800 ml of waterare added dropwise, yielding a dark precipitate. This mixture is againstirred at ambient temperature for 24 hours and filtered to give ayellow crystalline material which is recrystallized thrice from anethanol-water mixture to give an off-white crystalline material, mp106°-108° C., 3-{2-[4-(2-fluorobenzoyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₂ H₂₃ FN₂ O: 75.40%, C; 6.62%, H; 7.99%, N.Found: 75.41%, C; 6.59%, H; 8.03%, N.

EXAMPLE 17

A solution of 11.8 g of 3-(2-bromoethyl)-2-methylindole, 20.3 g of4-(4-toluyl)piperidine [Example 5(a)] in 500 ml of dimethylformamide istreated according to the manipulative procedure described in Example3(b) to give the off-white solid, mp 192°-194° C.,2-methyl-3-{2-[4-(4-toluyl)piperidyl]ethyl}indole from ethanol.

Analysis: Calculated for C₂₄ H₂₈ N₂ 0: 79.96%, C; 7.83%, H; 7.77%, N.Found: 79.82%, C; 7.80%, H; 7.69%, N.

EXAMPLE 18

A. By following the manipulative procedure described in Example 15(a),(b) and (c), 2-tolylnitrile is treated to produce 4-(2-toluyl)piperidinehydrochloride.

B. To a stirring solution of 4.2 g of 4-(2-toluyl)piperidinehydrochloride and 4.0 g of triethylamine in 150 ml of dimethylformamideis added 3.8 g of 3-(2bromoethyl)indole. The resulting solution isstirred at ambient temperature for 70 hours and stirring is continuedwhile 500 ml of water are added dropwise. An oil appears which isextracted from the solution with chloroform, the combined chloroformextracts are dried and the excess chloroform is removed, leaving an oilwhich crystallizes upon standing. The solid product is recrystallizedfrom cyclohexane and then twice from an ethanol-water mixture to giveflakes, mp 111°-112° C., 3-{2-[4-(2-toluyl)piperidly]ethyl}indole.

Analysis: Calculated for C₂₃ H₂₆ N₂ 0: 79.73%, C; 7.56%, H; 8.09%, N;Found: 79.83%, C; 7.69%, H; 8.14%, N.

EXAMPLE 19

A solution of 8.8 g of 3-(2-bromoethyl)-5-methoxy indole in 100 ml ofdimethylformamide is added to a stirring mixture of4-(4-toluyl)piperidine hydrochloride [Example 5(a)] and 10.1 g ofpotassium carbonate in 400 ml of dimethylformamide and the reactionmixture is stirred at ambient temperature for 80 hours and then at 50°C. for 10 additional hours. It is cooled to ambient temperature,filtered, and 2 liters of water are added dropwise to produce aprecipitate. The precipitate is triturated with ether and eluted with a5% methanol in benzene solution through a silica gel column. Theprecipitate is recrystallized from an ethanol-water mixture to giveoff-white crystals, mp 131°-133° C.,5-methoxy-3-{2-[4-(4-toluyl)piperidyl]ethyl}indole.

Analysis: Calculated for C₂₄ H₂₈ N₂ O₂ : 76.56%, C; 7.50%, H; 7.44%, N.Found: 76.36%, C; 7.45%, H; 7.19%, N.

EXAMPLE 20

A. By following the manipulative procedures outlined in Examples 1(a),(b), (c) and (d), a sample of biphenyl is treated to produce4-(4-phenylbenzoyl)piperidine.

B. A solution of 10.4 g of 4-(4-phenylbenzoyl)piperidine, 8.8 g of3-(2-bromoethyl)indole and 4.5 g of triethylamine in 300 ml ofdimethylformamide is treated according to the manipulative proceduresoutlined in Example 3(b) to produce3-{2-[4-(4-phenylbenzoyl)piperidyl]ethyl}indole. The indole isrecrystallized twice from an ethanol-water mixture (one charcoaltreatment), thrice from a pyridine-water mixture, and twice from anacetone-water mixture to give the product, mp 189°-192° C.

Analysis: Calculated for C₂₈ H₂₈ N₂ O: 82.32%, C; 6.91%, H; 6.85%, N;Found: 81.90%, C; 7.09%, H; 6.80%, N.

EXAMPLE 21

A. 8.7 g of oxalyl chloride are added dropwise to a stirring solution,cooled to about -10° C., of 12.0 g of 5,6-dimethoxy-2-methylindole in250 ml of ether. After addition is completed, the mixture is stirred for10 minutes, producing a bright orange precipitate of5,6-dimethoxy-2-methyl-3-indole glyoxylyl chloride which is immediatelyused for the next step.

B. The above ether suspension of5,6-dimethoxy-2-methyl-3-indoleglyoxylyl chloride is added portionwiseto a cooled stirring mixture of 4benzoylpiperidine [Example 9(a)], 150ml of water, 150 ml of chloroform and 25 g of potassium carbonate. Themixture is stirred for 16 hours at ambient temperature, the organiclayer is separated and the solvent is removed, leaving a brown oil whichis triturated with cyclohexane and then stirred for 16 hours with ether.A white solid results which is collected, dried and recrystallizedthrice from methanol to give the compound, mp 188°-190° C.,4-benzoyl-1-(5,6-dimethoxy-2-methylindol-3-ylglyoxyloyl)piperidine.

Analysis: Calculated for C₂₅ H₂₆ N₂ O₅ : 69.10%, C; 6.03%, H; 6.45%, N.Found: 68.98%, C; 6.20%, H; 6.38%, N.

C. A suspension of 20.2 g of4-benzoyl-1-(5,6-dimethoxy-2-methylindol-3-ylglyoxyloyl)piperidine in200 ml of tetrahydrofuran is added dropwise to a stirring solution,under nitrogen at a reflux, of 9.6 g of lithium aluminum hydride in 210ml of tetrahydrofuran. Stirring and refluxing is continued for 3 hours,the mixture is cooled in an ice bath and the excess hydride is destroyedwith water. The mixture is filtered and the filtrate is concentratedunder reduced pressure, leaving an off-white foam which is trituratedwith cyclohexane to give an off-white powder. The oxalate salt isprepared by dissolving the free base in isopropanol and slowly adding asolution of oxalic acid in isopropanol. The insoluble oxalate salt iscollected and recrystallized from ethanol to give white crystals, mp152°-154° C.,5,6-dimethoxy-2-methyl-3-[2-(4-phenylhydroxymethylpiperidyl)ethyl]indoleoxalate.

Analysis: Calculated for C₂₅ H₃₂ N₂ O₃ ·(CO₂ H)₂ : 65.04%, C; 6.87%, H;5.62%, N; Found: 65.02%, C; 6.87%, H; 5.61%, N.

EXAMPLE 22

A mixture of 6.2 g of 3-(3-bromopropyl)indole, 5.8 g of4-(4-fluorobenzoyl)piperidine, free base of Example 1d, 3.8 g ofpotassium carbonate in 65 ml of dimethylformamide is stirred undernitrogen at 50° C for 16 hours. The mixture is stirred while beingallowed to cool to ambient temperature and then 180 ml of water areadded slowly causing a yellow oil to separate. The supernatant aqueoussolution is decanted from the oil and the oil is taken up in ether, theethereal solution is washed with water and dried and the ether removedin vacuo leaving a white solid. The solid is dissolved in absoluteethanol, and HCl gas bubbled into the solution to produce a salt.Addition of ether to the solution causes the salt to precipitate. Thesalt is recrystallized from isopropanol to give the white solid, mp211°-213° C of 3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl}indolehydrochloride.

Analysis: Calculated for C₂₃ H₂₅ FNO₂ ·HCl: 68.69%, C; 6.54%, H; 6.99%,H; 8.84%, Cl; Found: 68.84%, C; 6.60%, H; 6.90%, H; 8.65%, Cl.

EXAMPLE 23

A sample of 3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl}indole, free baseof Example 22, is reduced and treated by the method described in Example2 to give 3-{3-[4-(4-fluorophenylhydroxymethyl)piperidyl]propyl}indole.

EXAMPLE 24

A sample of 3-(3-bromopropyl)-6-methoxy-2-methylindole and4-(3-fluorobenzoyl)piperidine are treated according to the methoddescribed in Example 1e to give6-methoxy-2-methyl-3-{3-[4-(4-fluorobenzoyl)piperidyl]-propyl}indolehydrochloride.

EXAMPLE 25

A sample of6-methoxy-2-methyl-3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl}indole,free base of Example 24, is reduced and treated by the method describedin Example 2 to give6-methoxy-2-methyl-3-{3-[4-(4-fluorophenylhydroxymethyl)piperidyl]propyl}indole.

We claim:
 1. A compound of the formula ##STR9## wherein X is ##STR10##or CHOH; R is hydrogen or methyl; R₁ and R₂ are the same or differentand stand for hydrogen, halogen, straight or branched chain alkyl of upto 5 carbon atoms, alkoxy of up to 5 carbon atoms, trifluoromethyl,hydroxy, phenoxy or phenyl; R₃ and R₄ are hydrogen or methoxy; n is theinteger 1 or 2; or an acid addition salt thereof prepared from apharmaceutically acceptable acid.
 2. A compound as defined in claim 1wherein R₁ and R₂ stand for hydrogen, chlorine, bromine, fluorine,straight or branched chain alkyl of up to 4 carbon atoms, methoxy,ethoxy, trifluoromethyl, hydroxy, phenoxy or phenyl.
 3. A compound asdefined in claim 2 wherein n is
 1. 4. A compound as defined in claim 2wherein n is
 2. 5. A compound as defined in claim 2 wherein R, R₃ and R₄are hydrogen.
 6. A compound as defined in claim 5 wherein n is
 1. 7. Acompound as defined in claim 5 wherein n is
 2. 8. The compound definedin claim 1 which is 3-{2-[4-(4-fluorobenzoyl)piperidyl]ethyl}indole oran acid addition salt thereof prepared from a pharmaceuticallyacceptable acid.
 9. The compound defined in claim 1 which is3-[2-(4-benzoylpiperidyl)ethyl]indole or an acid addition salt thereofprepared from a pharmaceutically acceptable acid.
 10. The compounddefined in claim 1 which is 3-{2-[4-(4-toluyl)piperidyl]ethyl}indole oran acid addition salt thereof prepared from a pharmaceuticallyacceptable acid.
 11. The compound defined in claim 1 which is3-{2-[4-(4-chlorobenzoyl)piperidyl]ethyl}indole or an acid addition saltthereof prepared from a pharmaceutically acceptable acid.
 12. Thecompound defined in claim 1 which is3-{2-[4-(4-fluorophenylhydroxymethyl)piperidyl]ethyl}indole or an acidaddition salt thereof prepared from a pharmaceutically acceptable acid.13. The compound defined in claim 1 which is3-{2-[4-(4-bromobenzoyl)piperidyl]ethyl}indole or an acid addition saltthereof prepared from a pharmaceutically acceptable acid.
 14. Thecompound defined in claim 1 which is3-{2-[4-(3,4-dimethylbenzoyl)piperidyl]ethyl}indole or an acid additionsalt thereof prepared from a pharmaceutically acceptable acid.
 15. Thecompound defined in claim 1 which is3-{2-[4-(2-fluoro-4-methylbenzoyl)piperidyl]ethyl}indole or an acidaddition salt thereof prepared from a pharmaceutically acceptable acid.16. The compound defined in claim 1 which is3-{2-[4-(2-fluorobenzoyl)piperidyl]ethyl}indole or an acid addition saltthereof prepared from a pharmaceutically acceptable acid.
 17. Thecompound defined in claim 1 which is3-{2-[4-(2-hydroxy-4-methoxybenzoyl)piperidyl]ethyl}indole or an acidaddition salt thereof prepared from a pharmaceutically acceptable acid.18. The compound defined in claim 1 which is3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl}indole or an acid additionsalt thereof prepared from a pharmaceutically acceptable acid.
 19. Amethod of depressing the central nervous system which comprisesadministering to a patient a pharmaceutically effective amount of acompound defined in claim
 1. 20. A pharmaceutical composition whichcomprises between 0.5 and about 70% by weight of a compound defined inclaim 1 as an essential active ingredient, the balance being apharmaceutically acceptable carrier therefor.